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1
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Omole TE, Nguyen HM, Marcinow A, Oo MM, Jahan N, Ssemaganda A, Severini G, Thomas KK, Celum C, Mugo N, Mujugira A, Kublin J, Corey L, Sivro A, Lingappa JR, Gray G, McKinnon LR. Pre-Human Immunodeficiency Virus (HIV) α4β7hi CD4+ T Cells and HIV Risk Among Heterosexual Individuals in Africa. J Infect Dis 2025; 231:e770-e780. [PMID: 39720913 PMCID: PMC11998548 DOI: 10.1093/infdis/jiae638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/13/2024] [Accepted: 12/20/2024] [Indexed: 12/26/2024] Open
Abstract
BACKGROUND CD4+ T cells expressing α4β7 are optimal targets for human immunodeficiency virus (HIV) infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men or people who inject drugs in the Americas, indicating need for further research. METHODS This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network [HVTN] 503) and East Africa (Partners Preexposure Prophylaxis/Couples' Observational Study [PP/COS]), quantifying α4β7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses. RESULTS Associations between α4β7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, α4β7hi expression was generally protective, particularly in Ugandans. Additionally, α4β7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, α4β7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T-cell decline, similar to what was observed previously in South Africa. CONCLUSIONS These findings suggest that α4β7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.
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Affiliation(s)
- Tosin E Omole
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Huong Mai Nguyen
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Agata Marcinow
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Myo Minn Oo
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Naima Jahan
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Aloysious Ssemaganda
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Giulia Severini
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | | | - Connie Celum
- Department of Global Health
- Departments of Medicine and Epidemiology, University of Washington, Seattle
| | - Nelly Mugo
- Department of Global Health
- Sexual Reproductive and Adolescent Child Health Research Program, Kenya Medical Research Institute, Nairobi
| | - Andrew Mujugira
- Department of Global Health
- Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - James Kublin
- HIV Vaccine Trials Network
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Lawrence Corey
- HIV Vaccine Trials Network
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Aida Sivro
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
- Mucosal Immunology Laboratory, Centre for the AIDS Program of Research in South Africa (CAPRISA), Durban
- JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba
- Department of Medical Microbiology, University of KwaZulu-Natal, Durban, South Africa
| | - Jairam R Lingappa
- Department of Global Health
- Departments of Medicine and Pediatrics, University of Washington, Seattle
| | - Glenda Gray
- HIV Vaccine Trials Network
- Office of the President, South African Medical Research Council, Cape Town
| | - Lyle R McKinnon
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
- Mucosal Immunology Laboratory, Centre for the AIDS Program of Research in South Africa (CAPRISA), Durban
- Department of Medical Microbiology and Immunology, University of Nairobi, Kenya
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2
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Rahman MA, Bissa M, Scinto H, Howe SE, Sarkis S, Ma ZM, Gutowska A, Jiang X, Luo CC, Schifanella L, Moles R, Silva de Castro I, Basu S, N'guessan KF, Williams LD, Becerra-Flores M, Doster MN, Hoang T, Choo-Wosoba H, Woode E, Sui Y, Tomaras GD, Paquin-Proulx D, Rao M, Talton JD, Kong XP, Zolla-Pazner S, Cardozo T, Franchini G, Berzofsky JA. Loss of HIV candidate vaccine efficacy in male macaques by mucosal nanoparticle immunization rescued by V2-specific response. Nat Commun 2024; 15:9102. [PMID: 39438480 PMCID: PMC11496677 DOI: 10.1038/s41467-024-53359-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024] Open
Abstract
Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIVmac251 acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17+NKp44+ innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.6% was preserved with V2-TTB NPs. The deleterious effects of NPs were linked to preferential recruitment of mucosal plasmacytoid dendritic cells (pDCs), reduction of protective mucosal NKp44+ ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ+NKG2A-NKp44-ILCs, and increased levels of mucosal activated Ki67+CD4+ T cells, a potential target for virus infection. V2-TTB NP mucosal boosting rescued vaccine efficacy, likely via high avidity V2-specific antibodies mediating ADCC, and higher frequencies of mucosal NKp44+ ILCs and of ∆V1gp120 binding antibody-secreting B cells in the rectal mucosa. These findings emphasize the central role of systemic immunization and mucosal V2-specific antibodies in the protection afforded by ΔV1 envelope immunogens and encourage careful evaluation of vaccine delivery platforms to avoid inducing immune responses favorable to HIV transmission.
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Affiliation(s)
- Mohammad Arif Rahman
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Massimiliano Bissa
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hanna Scinto
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Savannah E Howe
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sarkis Sarkis
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Zhong-Min Ma
- California National Primate Research Center, University of California, Davis, Davis, USA
| | - Anna Gutowska
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xunqing Jiang
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Christina C Luo
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Luca Schifanella
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ramona Moles
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Isabela Silva de Castro
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shraddha Basu
- United States Military HIV Research Program, CIDR, Walter Reed Army Institute of Research, Silver Spring, MD, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
| | - Kombo F N'guessan
- United States Military HIV Research Program, CIDR, Walter Reed Army Institute of Research, Silver Spring, MD, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
| | - LaTonya D Williams
- Center for Human Systems Immunology, Department of Surgery, Duke University School of Medicine, Durham, NC, USA
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
| | | | - Melvin N Doster
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tanya Hoang
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hyoyoung Choo-Wosoba
- Office of Collaborative Biostatistics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Emmanuel Woode
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yongjun Sui
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Georgia D Tomaras
- Center for Human Systems Immunology, Department of Surgery, Duke University School of Medicine, Durham, NC, USA
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
| | - Dominic Paquin-Proulx
- United States Military HIV Research Program, CIDR, Walter Reed Army Institute of Research, Silver Spring, MD, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
| | - Mangala Rao
- United States Military HIV Research Program, CIDR, Walter Reed Army Institute of Research, Silver Spring, MD, USA
| | | | - Xiang-Peng Kong
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Susan Zolla-Pazner
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, NY, New York, USA
| | - Timothy Cardozo
- New York University School of Medicine, NYU Langone Health, New York, NY, USA
| | - Genoveffa Franchini
- Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Jay A Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Govindan R, Stephenson KE. HIV Vaccine Development at a Crossroads: New B and T Cell Approaches. Vaccines (Basel) 2024; 12:1043. [PMID: 39340073 PMCID: PMC11435826 DOI: 10.3390/vaccines12091043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Despite rigorous scientific efforts over the forty years since the onset of the global HIV pandemic, a safe and effective HIV-1 vaccine remains elusive. The challenges of HIV vaccine development have proven immense, in large part due to the tremendous sequence diversity of HIV and its ability to escape from antiviral adaptive immune responses. In recent years, several phase 3 efficacy trials have been conducted, testing a similar hypothesis, e.g., that non-neutralizing antibodies and classical cellular immune responses could prevent HIV-1 acquisition. These studies were not successful. As a result, the field has now pivoted to bold novel approaches, including sequential immunization strategies to drive the generation of broadly neutralizing antibodies and human CMV-vectored vaccines to elicit MHC-E-restricted CD8+ T cell responses. Many of these vaccine candidates are now in phase 1 trials, with early promising results.
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Affiliation(s)
- Ramesh Govindan
- Division of Infectious Diseases and Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA;
| | - Kathryn E. Stephenson
- Division of Infectious Diseases and Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA;
- Harvard Medical School, Boston, MA 02115, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
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4
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Graciaa DS, Walsh SR, Rouphael N. Human Immunodeficiency Virus Vaccine: Promise and Challenges. Infect Dis Clin North Am 2024; 38:475-485. [PMID: 38876903 PMCID: PMC11305931 DOI: 10.1016/j.idc.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2024]
Abstract
Development of a safe and effective human immunodeficiency virus (HIV) vaccine is a persistent challenge despite decades of research. Previous strategies utilizing protein subunit and viral vector vaccines were safe but not protective. Current strategies seek to induce broadly neutralizing antibodies, with multiple early phase trials in progress seeking to achieve this through sequential vaccination, mRNA, or updated viral-vectored vaccines. A safe and effective vaccine is critical to ending the HIV epidemic.
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Affiliation(s)
- Daniel S Graciaa
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Hope Clinic of Emory Vaccine Center, 500 Irvin Court, Suite 200, Decatur, GA 30030, USA.
| | - Stephen R Walsh
- Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Nadine Rouphael
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Hope Clinic of Emory Vaccine Center, 500 Irvin Court, Suite 200, Decatur, GA 30030, USA
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5
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Beavis AC, Dienger-Stambaugh K, Briggs K, Chen Z, Abraham M, Spearman P, He B. A J Paramyxovirus-vectored HIV vaccine induces humoral and cellular responses in mice. Vaccine 2024; 42:2347-2356. [PMID: 38443277 DOI: 10.1016/j.vaccine.2024.02.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 02/17/2024] [Accepted: 02/23/2024] [Indexed: 03/07/2024]
Abstract
Human immunodeficiency virus (HIV) infects and depletes CD4+ T-cells, resulting in Acquired Immunodeficiency Syndrome (AIDS) and death. Despite numerous clinical trials, there is no licensed HIV vaccine. The HIV envelope glycoprotein (env) is a major target for vaccine development, especially for the development of antibody-mediated protection. In this study, we used J paramyxovirus (JPV) as a viral vector to express HIV-env. We replaced the JPV small hydrophobic (SH) gene with HIV-env (rJPV-env). Intranasal rJPV-env immunization induced anti-HIV-gp120 IgG antibodies in mice. Furthermore, we examined the immunogenicity of homologous and heterologous prime/boost regimens with rJPV-env, parainfluenza virus 5 (rPIV5)-vectored HIV-env, and HIV-Gag-Env virus-like particles (VLPs). The rJPV-env/rPIV5-env heterologous prime/boost regimen induced the strongest humoral and cellular responses. Introducing a third dose of immunization, mice that received a viral-vectored prime had high levels of HIV-env-specific cellular responses, with group rJPV-env/rPIV5-env/VLP having the highest. Together, this work indicates that a heterologous combination of viral-vectored HIV-env vaccines and a HIV-Gag-Env VLP induces high levels of humoral and cellular responses against HIV in mice.
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Affiliation(s)
- Ashley C Beavis
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, United States of America
| | - Krista Dienger-Stambaugh
- Infectious Diseases Division, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, United States of America
| | - Kelsey Briggs
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, United States of America
| | - Zhenhai Chen
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, United States of America
| | - Mathew Abraham
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, United States of America
| | - Paul Spearman
- Infectious Diseases Division, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, United States of America
| | - Biao He
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, United States of America.
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6
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Kaur A, Vaccari M. Exploring HIV Vaccine Progress in the Pre-Clinical and Clinical Setting: From History to Future Prospects. Viruses 2024; 16:368. [PMID: 38543734 PMCID: PMC10974975 DOI: 10.3390/v16030368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/08/2024] [Accepted: 02/21/2024] [Indexed: 04/01/2024] Open
Abstract
The human immunodeficiency virus (HIV) continues to pose a significant global health challenge, with millions of people affected and new cases emerging each year. While various treatment and prevention methods exist, including antiretroviral therapy and non-vaccine approaches, developing an effective vaccine remains the most crucial and cost-effective solution to combating the HIV epidemic. Despite significant advancements in HIV research, the HIV vaccine field has faced numerous challenges, and only one clinical trial has demonstrated a modest level of efficacy. This review delves into the history of HIV vaccines and the current efforts in HIV prevention, emphasizing pre-clinical vaccine development using the non-human primate model (NHP) of HIV infection. NHP models offer valuable insights into potential preventive strategies for combating HIV, and they play a vital role in informing and guiding the development of novel vaccine candidates before they can proceed to human clinical trials.
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Affiliation(s)
- Amitinder Kaur
- Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA;
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Monica Vaccari
- Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA;
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
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Miao X, Zhang L, Zhou P, Yu R, Zhang Z, Wang C, Guo H, Wang Y, Pan L, Liu X. Adenovirus-vectored PDCoV vaccines induce potent humoral and cellular immune responses in mice. Vaccine 2023; 41:6661-6671. [PMID: 37777448 DOI: 10.1016/j.vaccine.2023.09.053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 09/21/2023] [Accepted: 09/24/2023] [Indexed: 10/02/2023]
Abstract
Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes severe watery diarrhea, vomiting, dehydration and high mortality in piglets, resulting in significant economic losses by the global pig industry. Recently, PDCoV has also shown the potential for cross-species transmission. However, there are currently few vaccine studies and no commercially available vaccines for PDCoV. Hence, here, two novel human adenovirus 5 (Ad5)-vectored vaccines expressing codon-optimized forms of the PDCoV spike (S) glycoprotein (Ad-PD-tPA-Sopt) and S1 glycoprotein (Ad-PD-oriSIP-S1opt) were constructed, and their effects were evaluated via intramuscular (IM) injection in BALB/c mice with different doses and times. Both vaccines elicited robust humoral and cellular immune responses; moreover, Ad-PD-tPA-Sopt-vaccinated mice after two IM injections with 108 infectious units (IFU)/mouse had significantly higher anti-PDCoV-specific neutralizing antibody titers. In contrast, the mice immunized with Ad-PD-tPA-Sopt via oral gavage (OG) did not generate robust systemic and mucosal immunity. Thus, IM Ad-PD-tPA-Sopt administration is a promising strategy against PDCoV and provides useful information for future animal vaccine development.
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Affiliation(s)
- Xin Miao
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China
| | - Liping Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China
| | - Peng Zhou
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
| | - Ruiming Yu
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China
| | - Zhongwang Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China
| | - Cancan Wang
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China
| | - Huichen Guo
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
| | - Yonglu Wang
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
| | - Li Pan
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China.
| | - Xinsheng Liu
- State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China; National Center of Technology Innovation for Pigs, China.
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8
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Malahleha M, Laher F, Dilraj A, Smith P, Gray GE, Grove D, Odhiambo JA, Andrasik MP, Grunenberg NA, Moodie Z, Huang Y, Borate BR, Gillespie KM, Allen M, Atujuna M, Singh N, Kalonji D, Meintjes G, Kotze P, Bekker LG, Janes H. Risk Factors Associated with HIV Acquisition in Males Participating in HIV Vaccine Efficacy Trials in South Africa. AIDS Behav 2023; 27:3027-3037. [PMID: 36929319 PMCID: PMC10386918 DOI: 10.1007/s10461-023-04025-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2023] [Indexed: 03/17/2023]
Abstract
In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09% in HVTN 503) or identified as heterosexual (88.08% in HVTN 702). Annual HIV incidence was 1.39% in HVTN 503 (95% CI 0.76-2.32%) and 1.33% in HVTN 702 (95% CI 0.80-2.07%). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95% CI 3.44-11.62), transactional sex (HR 3.42, 95% CI 1.80-6.50), and non-heterosexual identity (HR 16.23, 95%CI 8.13-32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95% CI 4.99-45.04; p < 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex.
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Affiliation(s)
- Mookho Malahleha
- Setshaba Research Centre, Soshanguve, Tshwane, South Africa
- Synergy Biomed Research Institute, East London, Eastern Cape, South Africa
| | - Fatima Laher
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Athmanundh Dilraj
- Setshaba Research Centre, Soshanguve, Tshwane, South Africa.
- Setshaba Research Centre, 2088 Block H, Soshanguve, Pretoria, 0152, South Africa.
| | - Philip Smith
- The Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa
| | - Glenda E Gray
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- South African Medical Research Council, Cape Town, South Africa
| | - Doug Grove
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jackline A Odhiambo
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Michele P Andrasik
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Nicole A Grunenberg
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Zoe Moodie
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Yunda Huang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Bhavesh R Borate
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Kevin M Gillespie
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mary Allen
- Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Millicent Atujuna
- The Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa
| | - Nishanta Singh
- HIV and other Infectious Diseases Research Unit, South African Medical Research Council, Durban, South Africa
| | - Dishiki Kalonji
- South African Medical Research Council, Cape Town, South Africa
- HIV and other Infectious Diseases Research Unit, South African Medical Research Council, Durban, South Africa
| | - Graeme Meintjes
- Wellcome Centre for Infectious Diseases Research in Africa, Cape Town, South Africa
| | - Phillip Kotze
- Qhakaza Mbokodo Research Clinic, Ladysmith, South Africa
| | - Linda-Gail Bekker
- The Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa
| | - Holly Janes
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Wang H, Georgakopoulou A, Zhang W, Kim J, Gil S, Ehrhardt A, Lieber A. HDAd6/35++ - A new helper-dependent adenovirus vector platform for in vivo transduction of hematopoietic stem cells. Mol Ther Methods Clin Dev 2023; 29:213-226. [PMID: 37081854 PMCID: PMC10111954 DOI: 10.1016/j.omtm.2023.03.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/16/2023] [Indexed: 04/03/2023]
Abstract
In previous studies, we achieved safe and efficient in vivo hematopoietic stem cell (HSC) transduction in mobilized mice and macaques with intravenously injected helper-dependent adenovirus HDAd5/35++ vectors. These vectors are derivatives of serotype Ad5-containing CD46-affinity enhanced Ad35 fiber knob domains. Considering the impact of anti-Ad5/HDAd5/35++ neutralizing serum antibodies present in the human population, we generated HSC-retargeted HDAd6/35++ vectors derived from serotype 6. We found a lower prevalence and titers of serum anti-HDAd6/35++ in human samples compared with HDAd5/35++. HDAd6/35++ vectors efficiently transduced human and rhesus CD34+ cells in vitro. Intravenous injection of HDAd5/35++-GFP or HDAd6/35++-GFP vectors after G-CSF/AMD3100 mobilization of mice with established human hematopoiesis or human CD46 transgenic mice resulted in comparable GFP marking rates in HSCs in the bone marrow and spleen. In long-term in vivo HSC transduction and selection studies with integrating vectors, stable GFP expression in >75% of PBMCs was show for both vectors. In contrast with HDAd5/35++, undesired transduction of hepatocytes was minimal with HDAd6/35++. Furthermore, HDAd6/35++ allowed for efficient in vivo HSC transduction in Ad5-pre-immune mice. These features, together with the straightforward production of HDAd6/35++ vectors at high yield, make this new HDAd vector platform attractive for clinical translation of the in vivo approach.
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Affiliation(s)
- Hongjie Wang
- University of Washington, Department of Medicine, Division of Medical Genetics, Seattle, WA 98195, USA
| | - Aphrodite Georgakopoulou
- University of Washington, Department of Medicine, Division of Medical Genetics, Seattle, WA 98195, USA
| | - Wenli Zhang
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Jiho Kim
- University of Washington, Department of Medicine, Division of Medical Genetics, Seattle, WA 98195, USA
| | - Sucheol Gil
- University of Washington, Department of Medicine, Division of Medical Genetics, Seattle, WA 98195, USA
| | - Anja Ehrhardt
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - André Lieber
- University of Washington, Department of Medicine, Division of Medical Genetics, Seattle, WA 98195, USA
- University of Washington, Department of Laboratory Medicine & Pathology and Lab, Seattle, WA 98195, USA
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Rahman MA, Bissa M, Silva de Castro I, Helmold Hait S, Stamos JD, Bhuyan F, Hunegnaw R, Sarkis S, Gutowska A, Doster MN, Moles R, Hoang T, Miller Jenkins LM, Appella E, Venzon DJ, Choo-Wosoba H, Cardozo T, Baum MM, Appella DH, Robert-Guroff M, Franchini G. Vaccine plus microbicide effective in preventing vaginal SIV transmission in macaques. Nat Microbiol 2023; 8:905-918. [PMID: 37024617 PMCID: PMC10159859 DOI: 10.1038/s41564-023-01353-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 03/02/2023] [Indexed: 04/08/2023]
Abstract
The human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV)mac251 acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIVmac251, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected. In an arm of 18 vaccinated-only animals without microbicide, 40% of macaques remained uninfected. The combined SAMT-247/vaccine regimen was significantly more effective than vaccination alone. By analysing immune correlates of protection, we show that, by increasing zinc availability, SAMT-247 increases natural killer cytotoxicity and monocyte efferocytosis, and decreases T-cell activation to augment vaccine-induced protection.
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Affiliation(s)
- Mohammad Arif Rahman
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Massimiliano Bissa
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | | | - Sabrina Helmold Hait
- Section on Immune Biology of Retroviral Infection, National Cancer Institute, Bethesda, MD, USA
| | - James D Stamos
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Farzana Bhuyan
- Translational Autoinflammatory Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ruth Hunegnaw
- Section on Immune Biology of Retroviral Infection, National Cancer Institute, Bethesda, MD, USA
| | - Sarkis Sarkis
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Anna Gutowska
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Melvin N Doster
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Ramona Moles
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA
| | - Tanya Hoang
- Section on Immune Biology of Retroviral Infection, National Cancer Institute, Bethesda, MD, USA
| | - Lisa M Miller Jenkins
- Collaborative Protein Technology Resource, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD, USA
| | - Ettore Appella
- Chemical Immunology Section, National Cancer Institute, Bethesda, MD, USA
| | - David J Venzon
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Hyoyoung Choo-Wosoba
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Timothy Cardozo
- New York University School of Medicine, NYU Langone Health, New York, NY, USA
| | - Marc M Baum
- Oak Crest Institute of Science, Monrovia, CA, USA
| | - Daniel H Appella
- Synthetic Bioactive Molecules Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Marjorie Robert-Guroff
- Section on Immune Biology of Retroviral Infection, National Cancer Institute, Bethesda, MD, USA
| | - Genoveffa Franchini
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD, USA.
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11
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Rahman MA, Becerra-Flores M, Patskovsky Y, Silva de Castro I, Bissa M, Basu S, Shen X, Williams LD, Sarkis S, N’guessan KF, LaBranche C, Tomaras GD, Aye PP, Veazey R, Paquin-Proulx D, Rao M, Franchini G, Cardozo T. Cholera toxin B scaffolded, focused SIV V2 epitope elicits antibodies that influence the risk of SIV mac251 acquisition in macaques. Front Immunol 2023; 14:1139402. [PMID: 37153584 PMCID: PMC10160393 DOI: 10.3389/fimmu.2023.1139402] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
Introduction An efficacious HIV vaccine will need to elicit a complex package of innate, humoral, and cellular immune responses. This complex package of responses to vaccine candidates has been studied and yielded important results, yet it has been a recurring challenge to determine the magnitude and protective effect of specific in vivo immune responses in isolation. We therefore designed a single, viral-spike-apical, epitope-focused V2 loop immunogen to reveal individual vaccine-elicited immune factors that contribute to protection against HIV/SIV. Method We generated a novel vaccine by incorporating the V2 loop B-cell epitope in the cholera toxin B (CTB) scaffold and compared two new immunization regimens to a historically protective 'standard' vaccine regimen (SVR) consisting of 2xDNA prime boosted with 2xALVAC-SIV and 1xΔV1gp120. We immunized a cohort of macaques with 5xCTB-V2c vaccine+alum intramuscularly simultaneously with topical intrarectal vaccination of CTB-V2c vaccine without alum (5xCTB-V2/alum). In a second group, we tested a modified version of the SVR consisting of 2xDNA prime and boosted with 1xALVAC-SIV and 2xALVAC-SIV+CTB-V2/alum, (DA/CTB-V2c/alum). Results In the absence of any other anti-viral antibodies, V2c epitope was highly immunogenic when incorporated in the CTB scaffold and generated highly functional anti-V2c antibodies in the vaccinated animals. 5xCTB-V2c/alum vaccination mediated non-neutralizing ADCC activity and efferocytosis, but produced low avidity, trogocytosis, and no neutralization of tier 1 virus. Furthermore, DA/CTB-V2c/alum vaccination also generated lower total ADCC activity, avidity, and neutralization compared to the SVR. These data suggest that the ΔV1gp120 boost in the SVR yielded more favorable immune responses than its CTB-V2c counterpart. Vaccination with the SVR generates CCR5- α4β7+CD4+ Th1, Th2, and Th17 cells, which are less likely to be infected by SIV/HIV and likely contributed to the protection afforded in this regimen. The 5xCTB-V2c/alum regimen likewise elicited higher circulating CCR5- α4β7+ CD4+ T cells and mucosal α4β7+ CD4+ T cells compared to the DA/CTB-V2c/alum regimen, whereas the first cell type was associated with reduced risk of viral acquisition. Conclusion Taken together, these data suggest that individual viral spike B-cell epitopes can be highly immunogenic and functional as isolated immunogens, although they might not be sufficient on their own to provide full protection against HIV/SIV infection.
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Affiliation(s)
- Mohammad Arif Rahman
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH Bethesda, MD, United States
| | - Manuel Becerra-Flores
- NYU Langone Health, New York University School of Medicine, New York, NY, United States
| | - Yury Patskovsky
- NYU Langone Health, New York University School of Medicine, New York, NY, United States
| | - Isabela Silva de Castro
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH Bethesda, MD, United States
| | - Massimiliano Bissa
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH Bethesda, MD, United States
| | - Shraddha Basu
- United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Xiaoying Shen
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - LaTonya D. Williams
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Sarkis Sarkis
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH Bethesda, MD, United States
| | - Kombo F. N’guessan
- United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Celia LaBranche
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Georgia D. Tomaras
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, United States
| | - Pyone Pyone Aye
- Veterinary Medicine, Tulane National Primate Research Center, Covington, LA, United States
| | - Ronald Veazey
- Division of Comparative Pathology, Department of Pathology and Laboratory Medicine, Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, United States
| | - Dominic Paquin-Proulx
- United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Mangala Rao
- United States Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States
| | - Genoveffa Franchini
- Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH Bethesda, MD, United States
| | - Timothy Cardozo
- NYU Langone Health, New York University School of Medicine, New York, NY, United States
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Laher F, Otwombe K, Mokwena O, Bekker LG, Allen M. Use of Varied Screening Risk Criteria and HIV Incidence in Phase 1 and 2 HIV Vaccine Trials in South Africa. AIDS Behav 2023; 27:1314-1320. [PMID: 36287343 PMCID: PMC10038814 DOI: 10.1007/s10461-022-03867-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/14/2022] [Indexed: 11/01/2022]
Abstract
Many early phase HIV prevention studies define HIV risk-related eligibility criteria. We conducted a retrospective review of HIV Vaccine Trials Network (HVTN) Phase 1 and 2 HIV vaccine clinical trials completed in South Africa from 2003 to 2020, evaluating HIV incidence by protocol-defined risk criteria. Comparisons between groups controlled for age, gender and year of trial initiation. Across 12 trials, 1 did not specify risk criteria, and 11 specified various low risk criteria thematically categorized under sexual behaviors, clinical characteristics, and/or drug use behavior. Of the 11 trials, 6 used low sexual risk eligibility criteria standardized by the HVTN in 2009. Of the 1249 participants, median age 23.0 years, 66% were enrolled with the HVTN 2009 standardized low risk criteria, 15% using other sets of low risk criteria, and 19% using no risk criteria. Compared with the standardized low risk criteria group [2.3], HIV incidence per 100 person-years was significantly higher in the non-standardized low risk criteria group [5.0] and in the no risk criteria group [4.8]. In South Africa, cohorts with low HIV incidence can be identified primarily through sexual behavior and clinical characteristics.
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Affiliation(s)
- Fatima Laher
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Soweto, South Africa.
| | - Kennedy Otwombe
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Soweto, South Africa
- School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Ofentse Mokwena
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Soweto, South Africa
| | - Linda-Gail Bekker
- The Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa
| | - Mary Allen
- Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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13
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Li S, Zhang MY, Yuan J, Zhang YX. Nano-vaccines for gene delivery against HIV-1 infection. Expert Rev Vaccines 2023; 22:315-326. [PMID: 36945780 DOI: 10.1080/14760584.2023.2193266] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
INTRODUCTION Over the last four decades, human immunodeficiency virus type 1 (HIV-1) infection has been a major public health concern. It is acknowledged that an effective vaccine remains the best hope for eliminating the HIV-1 pandemic. The prophylaxis of HIV-1 infection remains a central theme because of the absence of an available HIV-1 vaccine. The incapability of conventional delivery strategies to induce potent immunity is a crucial task to overcome and ultimately lead to a major obstacle in HIV-1 vaccine research. AREAS COVERED The literature search was conducted in the following databases: PubMed, Web of Science, and Embase. Nano-platforms based vaccines have proven prophylaxis of various diseases for effectively activating the immune system. Nano-vaccines, including non-viral and viral vectored nano-vaccines, are in a position to improve the effectiveness of HIV-1 antigen delivery and enhance the innate and adaptive immune responses against HIV-1. Compared to traditional vaccination strategies, genetic immunization can elicit a long-term immune response to provide protective immunity for HIV-1 prevention. EXPERT OPINION The research progress on nano-vaccines for gene delivery against HIV-1 was discussed. The vaccine strategies based on nano-platforms that are being applied to stimulate effective HIV-1-specific cellular and humoral immune responses were particularly emphasized.
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Affiliation(s)
- Shuang Li
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Meng-Yue Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jie Yuan
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yi-Xuan Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
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14
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Haynes BF, Wiehe K, Borrow P, Saunders KO, Korber B, Wagh K, McMichael AJ, Kelsoe G, Hahn BH, Alt F, Shaw GM. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies. Nat Rev Immunol 2023; 23:142-158. [PMID: 35962033 PMCID: PMC9372928 DOI: 10.1038/s41577-022-00753-w] [Citation(s) in RCA: 182] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2022] [Indexed: 01/07/2023]
Abstract
After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1-host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success.
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Affiliation(s)
- Barton F Haynes
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
- Department of Immunology, Duke University of School of Medicine, Durham, NC, USA.
| | - Kevin Wiehe
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Persephone Borrow
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Kevin O Saunders
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Bette Korber
- T-6: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
- New Mexico Consortium, Los Alamos, NM, USA
| | - Kshitij Wagh
- T-6: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
- New Mexico Consortium, Los Alamos, NM, USA
| | - Andrew J McMichael
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Garnett Kelsoe
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Immunology, Duke University of School of Medicine, Durham, NC, USA
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Beatrice H Hahn
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Frederick Alt
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA, USA
| | - George M Shaw
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
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15
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Molecular Mechanism of Adenovirus Late Protein L4-100K Chaperones the Trimerization of Hexon. J Virol 2023; 97:e0146722. [PMID: 36475768 PMCID: PMC9888260 DOI: 10.1128/jvi.01467-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Assembly of the adenovirus capsid protein hexon depends on the assistance of the molecular chaperone L4-100K. However, the chaperone mechanisms remain unclear. In this study, we found that L4-100K was involved in the hexon translation process and could prevent hexon degradation by the proteasome in cotransfected human cells. Two nonadjacent domains, 84-133 and 656-697, at the N-terminal and C-terminal regions of human adenovirus type 5 L4-100K, respectively, were found to be crucial and cooperatively responsible for hexon trimer expression and assembly. These two chaperone-related domains were conserved in the sequence of L4-100K and in the function of hexon assembly across different adenovirus serotypes. Different degrees of cross-activity of hexon trimerization with different serotypes were detected in subgroups B, C, and D, which were proven to be controlled by the interaction between the C-terminal chaperone-related domain of L4-100K and hypervariable regions (HVR) of hexon. Additionally, HVR-chimeric hexon mutants were successfully assembled with the assistance of the 1-697 mutant. Structural analysis of 656-697 by nuclear magnetic resonance and structural prediction of L4-100K using Robetta showed that the two conserved domains are mainly composed of α-helices and are located on the surface of the highly folded core region. Our research provides a more complete understanding of hexon assembly and guidance for the development of hexon-chimeric adenovirus vectors that will be safer, smarter, and more efficient. IMPORTANCE Adenovirus vectors have been widely used in clinical trials of vaccines and gene therapy, although some deficiencies remain. Chimeric modification of the hexon was expected to improve the potency of preexisting immune evasion and targeting, but in many cases, viral packaging is prevented by the inability of the chimeric hexon to assemble correctly. So far, few studies have examined the mechanisms of hexon trimer assembly. Here, we show how the chaperone protein L4-100K contributes to the assembly of the adenovirus capsid protein hexon, and these data will provide a guide for novel adenovirus vector design and development, as we desired.
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16
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New vector and vaccine platforms: mRNA, DNA, viral vectors. Curr Opin HIV AIDS 2022; 17:338-344. [DOI: 10.1097/coh.0000000000000763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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17
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Ura T, Takeuchi M, Kawagoe T, Mizuki N, Okuda K, Shimada M. Current Vaccine Platforms in Enhancing T-Cell Response. Vaccines (Basel) 2022; 10:1367. [PMID: 36016254 PMCID: PMC9413345 DOI: 10.3390/vaccines10081367] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/28/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
The induction of T cell-mediated immunity is crucial in vaccine development. The most effective vaccine is likely to employ both cellular and humoral immune responses. The efficacy of a vaccine depends on T cells activated by antigen-presenting cells. T cells also play a critical role in the duration and cross-reactivity of vaccines. Moreover, pre-existing T-cell immunity is associated with a decreased severity of infectious diseases. Many technical and delivery platforms have been designed to induce T cell-mediated vaccine immunity. The immunogenicity of vaccines is enhanced by controlling the kinetics and targeted delivery. Viral vectors are attractive tools that enable the intracellular expression of foreign antigens and induce robust immunity. However, it is necessary to select an appropriate viral vector considering the existing anti-vector immunity that impairs vaccine efficacy. mRNA vaccines have the advantage of rapid and low-cost manufacturing and have been approved for clinical use as COVID-19 vaccines for the first time. mRNA modification and nanomaterial encapsulation can help address mRNA instability and translation efficacy. This review summarizes the T cell responses of vaccines against various infectious diseases based on vaccine technologies and delivery platforms and discusses the future directions of these cutting-edge platforms.
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Affiliation(s)
- Takehiro Ura
- Department of Ophthalmology and Visual Science, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Masaki Takeuchi
- Department of Ophthalmology and Visual Science, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Tatsukata Kawagoe
- Department of Ophthalmology and Visual Science, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
- Department of Ophthalmology and Visual Science, School of Medicine, St. Marianna University, Kawazaki 216-8511, Japan
| | - Nobuhisa Mizuki
- Department of Ophthalmology and Visual Science, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Kenji Okuda
- Department of Molecular Biodefense Research, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Masaru Shimada
- Department of Molecular Biodefense Research, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
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18
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Folegatti PM, Jenkin D, Morris S, Gilbert S, Kim D, Robertson JS, Smith ER, Martin E, Gurwith M, Chen RT, For the Benefit-Risk Assessment of VAccines by TechnolOgy Working Group BRAVATO, ex-V3SWG). Vaccines based on the replication-deficient simian adenoviral vector ChAdOx1: Standardized template with key considerations for a risk/benefit assessment. Vaccine 2022; 40:5248-5262. [PMID: 35715352 PMCID: PMC9194875 DOI: 10.1016/j.vaccine.2022.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/10/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023]
Abstract
Replication-deficient adenoviral vectors have been under investigation as a platform technology for vaccine development for several years and have recently been successfully deployed as an effective COVID-19 counter measure. A replication-deficient adenoviral vector based on the simian adenovirus type Y25 and named ChAdOx1 has been evaluated in several clinical trials since 2012. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) was formed to evaluate the safety and other key features of new platform technology vaccines. This manuscript reviews key features of the ChAdOx1-vectored vaccines. The simian adenovirus Y25 was chosen as a strategy to circumvent pre-existing immunity to common human adenovirus serotypes which could impair immune responses induced by adenoviral vectored vaccines. Deletion of the E1 gene renders the ChAdOx1 vector replication incompetent and further genetic engineering of the E3 and E4 genes allows for increased insertional capability and optimizes vaccine manufacturing processes. ChAdOx1 vectored vaccines can be manufactured in E1 complementing cell lines at scale and are thermostable. The first ChAdOx1 vectored vaccines approved for human use, against SARS-CoV-2, received emergency use authorization in the UK on 30th December 2020, and is now approved in more than 180 countries. Safety data were compiled from phase I-III clinical trials of ChAdOx1 vectored vaccines expressing different antigens (influenza, tuberculosis, malaria, meningococcal B, prostate cancer, MERS-CoV, Chikungunya, Zika and SARS-CoV-2), conducted by the University of Oxford, as well as post marketing surveillance data for the COVID-19 Oxford-AstraZeneca vaccine. Overall, ChAdOx1 vectored vaccines have been well tolerated. Very rarely, thrombosis with thrombocytopenia syndrome (TTS), capillary leak syndrome (CLS), immune thrombocytopenia (ITP), and Guillain-Barre syndrome (GBS) have been reported following mass administration of the COVID-19 Oxford-AstraZeneca vaccine. The benefits of this COVID-19 vaccination have outweighed the risks of serious adverse events in most settings, especially with mitigation of risks when possible. Extensive immunogenicity clinical evaluation of ChAdOx1 vectored vaccines reveal strong, durable humoral and cellular immune responses to date; studies to refine the COVID-19 protection (e.g., via homologous/heterologous booster, fractional dose) are also underway. New prophylactic and therapeutic vaccines based on the ChAdOx1 vector are currently undergoing pre-clinical and clinical assessment, including vaccines against viral hemorrhagic fevers, Nipah virus, HIV, Hepatitis B, amongst others.
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Affiliation(s)
| | | | | | | | - Denny Kim
- Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA, USA
| | - James S. Robertson
- Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA, USA
| | - Emily R. Smith
- Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA, USA,Corresponding author
| | - Emalee Martin
- Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA, USA
| | - Marc Gurwith
- Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA, USA
| | - Robert T. Chen
- Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA, USA
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19
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Lin LY, Carapito R, Su B, Moog C. Fc receptors and the diversity of antibody responses to HIV infection and vaccination. Genes Immun 2022; 23:149-156. [PMID: 35688931 PMCID: PMC9388370 DOI: 10.1038/s41435-022-00175-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/19/2022] [Accepted: 05/24/2022] [Indexed: 11/23/2022]
Abstract
The development of an effective vaccine against HIV is desperately needed. The successive failures of HIV vaccine efficacy trials in recent decades have shown the difficulty of inducing an appropriate protective immune response to fight HIV. Different correlates of antibody parameters associated with a decreased risk of HIV-1 acquisition have been identified. However, these parameters are difficult to reproduce and improve, possibly because they have an intricate and combined action. Here, we describe the numerous antibody (Ab) functions associated with HIV-1 protection and report the interrelated parameters regulating their complex functions. Indeed, besides neutralizing and Fc-mediated activity, additional factors such as Ab type, concentration and kinetics of induction, and Fc-receptor expression and binding capacity also influence the protective effect conferred by Abs. As these parameters were described to be associated with ethnicity, age and sex, these additional factors must be considered for the development of an effective immune response. Therefore, future vaccine designs need to consider these multifaceted Ab functions together with the demographic attributes of the patient populations.
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Affiliation(s)
- Li-Yun Lin
- Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Raphael Carapito
- Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Bin Su
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Christiane Moog
- Laboratoire d'ImmunoRhumatologie Moléculaire, Institut national de la santé et de la recherche médicale (INSERM) UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. .,Vaccine Research Institute (VRI), Créteil, France.
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20
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Coughlan L, Kremer EJ, Shayakhmetov DM. Adenovirus-based vaccines-a platform for pandemic preparedness against emerging viral pathogens. Mol Ther 2022; 30:1822-1849. [PMID: 35092844 PMCID: PMC8801892 DOI: 10.1016/j.ymthe.2022.01.034] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 11/24/2022] Open
Abstract
Zoonotic viruses continually pose a pandemic threat. Infection of humans with viruses for which we typically have little or no prior immunity can result in epidemics with high morbidity and mortality. These epidemics can have public health and economic impact and can exacerbate civil unrest or political instability. Changes in human behavior in the past few decades-increased global travel, farming intensification, the exotic animal trade, and the impact of global warming on animal migratory patterns, habitats, and ecosystems-contribute to the increased frequency of cross-species transmission events. Investing in the pre-clinical advancement of vaccine candidates against diverse emerging viral threats is crucial for pandemic preparedness. Replication-defective adenoviral (Ad) vectors have demonstrated their utility as an outbreak-responsive vaccine platform during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Ad vectors are easy to engineer; are amenable to rapid, inexpensive manufacturing; are relatively safe and immunogenic in humans; and, importantly, do not require specialized cold-chain storage, making them an ideal platform for equitable global distribution or stockpiling. In this review, we discuss the progress in applying Ad-based vaccines against emerging viruses and summarize their global safety profile, as reflected by their widespread geographic use during the SARS-CoV-2 pandemic.
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Affiliation(s)
- Lynda Coughlan
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Center for Vaccine Development and Global Health (CVD), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Eric J Kremer
- Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS 5535, Montpellier, France.
| | - Dmitry M Shayakhmetov
- Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Discovery and Developmental Therapeutics Program, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
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21
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Zhang L, Gilbert PB, Capparelli E, Huang Y. Simulation-Based Pharmacokinetics Sampling Design for Evaluating Correlates of Prevention Efficacy of Passive HIV Monoclonal Antibody Prophylaxis. Stat Biopharm Res 2022; 14:611-625. [PMID: 36684526 PMCID: PMC9856202 DOI: 10.1080/19466315.2021.1919196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We address sampling design of population pharmacokinetics (popPK) experiments in the context of two ongoing phase 2b efficacy trials that evaluate the efficacy of VRC01 (vs. placebo) in reducing the rate of HIV infection among 4625 participants. Blood samples are collected at up to 22 study visits from all participants for immediate HIV diagnosis as the primary trial outcome, and stored for future outcome-dependent marker measurements. A key secondary objective of the trials is to evaluate correlates of prevention efficacy among a sub-cohort of VRC01 recipients in terms of whether the current value of VRC01 serum concentration is associated with the instantaneous rate of HIV infection. To accomplish this, concentrations on a daily grid are estimated via non-linear mixed effects popPK modeling of observed 4-weekly concentrations. Given the impracticality of measuring concentrations in all stored blood samples, we devised a simulation-based sampling design framework to evaluate the impact of sub-cohort sample sizes (m) and sampling schemes of time-points on the accuracy and precision of the popPK model parameters. We accounted for specific study schedules and heterogeneity in participants' characteristics and study adherence patterns. We found that with m = 120, reasonably unbiased and consistent estimates of most fixed and random effect terms could be obtained without complete sampling of all 22 time-points, even under low study adherence (about half of the 4-weekly visits missing per participant). The described simulation framework is not only novel in its application to popPK sampling design for studying correlates of prevention efficacy in a subcohort of the parent trial, but also flexible in accommodating real-life study setup options, and can be generalized to other single- or multiple-dose PK sampling design settings.
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Affiliation(s)
- Lily Zhang
- Vaccine and Infectious Disease Division, Fred Hutchinson Research Center, Seattle, USA
| | - Peter B. Gilbert
- Vaccine and Infectious Disease Division, Fred Hutchinson Research Center, Seattle, USA,Department of Biostatistics, University of Washington, Seattle, USA
| | | | - Yunda Huang
- Vaccine and Infectious Disease Division, Fred Hutchinson Research Center, Seattle, USA,Department of Global Health, University of Washington, Seattle, USA,Corresponding author: Yunda Huang, Ph.D. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA. Tel: 001-206-667-5780
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22
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Lassaunière R, Tiemessen CT. FcγR Genetic Variation and HIV-1 Vaccine Efficacy: Context And Considerations. Front Immunol 2021; 12:788203. [PMID: 34975881 PMCID: PMC8714752 DOI: 10.3389/fimmu.2021.788203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/29/2021] [Indexed: 12/02/2022] Open
Abstract
Receptors for the crystallisable fragment (Fc) of immunoglobulin (Ig) G, Fcγ receptors (FcγRs), link the humoral and cellular arms of the immune response, providing a diverse armamentarium of antimicrobial effector functions. Findings from HIV-1 vaccine efficacy trials highlight the need for further study of Fc-FcR interactions in understanding what may constitute vaccine-induced protective immunity. These include host genetic correlates identified within the low affinity Fcγ-receptor locus in three HIV-1 efficacy trials – VAX004, RV144, and HVTN 505. This perspective summarizes our present knowledge of FcγR genetics in the context of findings from HIV-1 efficacy trials, and draws on genetic variation described in other contexts, such as mother-to-child HIV-1 transmission and HIV-1 disease progression, to explore the potential contribution of FcγR variability in modulating different HIV-1 vaccine efficacy outcomes. Appreciating the complexity and the importance of the collective contribution of variation within the FCGR gene locus is important for understanding the role of FcγRs in protection against HIV-1 acquisition.
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Affiliation(s)
- Ria Lassaunière
- Virus and Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, Denmark
- *Correspondence: Caroline T. Tiemessen, ; Ria Lassaunière,
| | - Caroline T. Tiemessen
- Centre for HIV and STI’s, National Institute for Communicable Diseases, Johannesburg, South Africa
- Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- *Correspondence: Caroline T. Tiemessen, ; Ria Lassaunière,
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23
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Ensoli B, Moretti S, Borsetti A, Maggiorella MT, Buttò S, Picconi O, Tripiciano A, Sgadari C, Monini P, Cafaro A. New insights into pathogenesis point to HIV-1 Tat as a key vaccine target. Arch Virol 2021; 166:2955-2974. [PMID: 34390393 PMCID: PMC8363864 DOI: 10.1007/s00705-021-05158-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/09/2021] [Indexed: 02/07/2023]
Abstract
Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis.
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Affiliation(s)
- Barbara Ensoli
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Sonia Moretti
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Alessandra Borsetti
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Maria Teresa Maggiorella
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Stefano Buttò
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Orietta Picconi
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Antonella Tripiciano
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Cecilia Sgadari
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Paolo Monini
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Aurelio Cafaro
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
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24
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Buttery JP. Developing standard safety outcomes for COVID-19 vaccines. Vaccine 2021; 39:3025-3027. [PMID: 33888324 PMCID: PMC7953438 DOI: 10.1016/j.vaccine.2021.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 11/15/2022]
Affiliation(s)
- Jim P Buttery
- Centre for Health Informatics, Royal Children's Hospital, Department of Paediatrics, University of Melbourne, Murdoch Childrens Research Institute, Flemington Rd, Parkville 3052, Victoria, Australia.
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25
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Abstract
HIV is a virus that remains a major health concern and results in an infection that has no cure even after over 30 years since its discovery. As such, HIV vaccine discovery continues to be an area of intensive research. In this review, we summarize the most recent HIV vaccine efficacy trials, clinical trials initiated within the last 3 years, and discuss prominent improvements that have been made in prophylactic HIV vaccine designs.
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Affiliation(s)
- Jeong Hyun Lee
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA; Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA.
| | - Shane Crotty
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA; Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
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26
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Apaydin EA, Richardson AS, Baxi S, Vockley J, Akinniranye O, Ross R, Larkin J, Motala A, Azhar G, Hempel S. An evidence map of randomised controlled trials evaluating genetic therapies. BMJ Evid Based Med 2020; 26:bmjebm-2020-111448. [PMID: 33172937 DOI: 10.1136/bmjebm-2020-111448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/18/2020] [Indexed: 01/11/2023]
Abstract
OBJECTIVES Genetic therapies replace or inactivate disease-causing genes or introduce new or modified genes. These therapies have the potential to cure in a single application rather than treating symptoms through repeated administrations. This evidence map provides a broad overview of the genetic therapies that have been evaluated in randomised controlled trials (RCTs) for efficacy and safety. ELIGIBILITY CRITERIA Two independent reviewers screened publications using predetermined eligibility criteria. Study details and data on safety and efficacy were abstracted from included trials. Results were visualised in an evidence map. INFORMATION SOURCES We searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov and grey literature to November 2018. RISK OF BIAS Only RCTs were included in this review to reduce the risk of selection bias in the evaluation of genetic therapy safety and efficacy. INCLUDED STUDIES We identified 119 RCTs evaluating genetic therapies for a variety of clinical conditions. SYNTHESIS OF RESULTS On average, samples included 107 participants (range: 1-1022), and were followed for 15 months (range: 0-124). Interventions using adenoviruses (40%) to treat cardiovascular diseases (29%) were the most common. DESCRIPTION OF THE EFFECT In RCTs reporting safety and efficacy outcomes, in the majority (60%) genetic therapies were associated with improved symptoms but in nearly half (45%) serious adverse event (SAEs) were also reported. Improvement was reported in trials treating cancer, cardiovascular, ocular and muscular diseases. However, only 19 trials reported symptom improvement for at least 1 year. STRENGTHS AND LIMITATIONS OF EVIDENCE This is the first comprehensive evidence map of RCTs evaluating the safety and efficacy of genetic therapies. Evidence for long-term effectiveness and safety is still sparse. This lack of evidence has implications for the use, ethics, pricing and logistics of genetic therapies. INTERPRETATION This evidence map provides a broad overview of research studies that allow strong evidence statements regarding the safety and efficacy of genetic therapies. Most interventions improve symptoms, but SAE are also common. More research is needed to evaluate genetic therapies with regard to the potential to cure diseases.
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Affiliation(s)
- Eric A Apaydin
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
- Center for the Study of Healthcare Innovation, Implementation and Policy, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Andrea S Richardson
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Pittsburgh, Pennsylvania, USA
| | - Sangita Baxi
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
| | - Jerry Vockley
- Division of Medical Genetics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Olamigoke Akinniranye
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
| | - Rachel Ross
- West Los Angeles Medical Center, Kaiser Foundation Hospitals, Los Angeles, California, USA
| | - Jody Larkin
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
| | - Aneesa Motala
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
| | - Gulrez Azhar
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
| | - Susanne Hempel
- Southern California Evidence-based Practice Center, Health Care, RAND Corporation, Santa Monica, California, USA
- Southern California Evidence Review Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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27
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Affiliation(s)
- Eric J Kremer
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier - CNRS, Montpellier, France.
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28
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SARS-CoV-2 vaccine research and development: Conventional vaccines and biomimetic nanotechnology strategies. Asian J Pharm Sci 2020; 16:136-146. [PMID: 32905011 PMCID: PMC7462629 DOI: 10.1016/j.ajps.2020.08.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/16/2020] [Accepted: 08/12/2020] [Indexed: 02/08/2023] Open
Abstract
The development of a massively producible vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, is essential for stopping the current coronavirus disease (COVID-19) pandemic. A vaccine must stimulate effective antibody and T cell responses in vivo to induce long-term protection. Scientific researchers have been developing vaccine candidates for the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) since the outbreaks of these diseases. The prevalence of new biotechnologies such as genetic engineering has shed light on the generation of vaccines against novel viruses. In this review, we present the status of the development of coronavirus vaccines, focusing particularly on the biomimetic nanoparticle technology platform, which is likely to have a major role in future developments of personalized medicine.
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29
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Zhu FC, Li YH, Guan XH, Hou LH, Wang WJ, Li JX, Wu SP, Wang BS, Wang Z, Wang L, Jia SY, Jiang HD, Wang L, Jiang T, Hu Y, Gou JB, Xu SB, Xu JJ, Wang XW, Wang W, Chen W. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020; 395:1845-1854. [PMID: 32450106 PMCID: PMC7255193 DOI: 10.1016/s0140-6736(20)31208-3] [Citation(s) in RCA: 992] [Impact Index Per Article: 198.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. METHODS We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. FINDINGS Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. INTERPRETATION The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. FUNDING National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.
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Affiliation(s)
- Feng-Cai Zhu
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.
| | - Yu-Hua Li
- China National Institute for Food and Drug Control, Beijing, China
| | - Xu-Hua Guan
- Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Li-Hua Hou
- Beijing Institute of Biotechnology, Beijing, China
| | - Wen-Juan Wang
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Jing-Xin Li
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Shi-Po Wu
- Beijing Institute of Biotechnology, Beijing, China
| | - Bu-Sen Wang
- Beijing Institute of Biotechnology, Beijing, China
| | - Zhao Wang
- Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Lei Wang
- Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Si-Yue Jia
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Hu-Dachuan Jiang
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Ling Wang
- China National Institute for Food and Drug Control, Beijing, China
| | - Tao Jiang
- Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | - Yi Hu
- Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | | | - Sha-Bei Xu
- Clinical Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun-Jie Xu
- Beijing Institute of Biotechnology, Beijing, China
| | - Xue-Wen Wang
- Shanghai Canming Medical Technology, Shanghai, China
| | - Wei Wang
- Clinical Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Wei Chen
- Beijing Institute of Biotechnology, Beijing, China.
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Korber B, Fischer W. T cell-based strategies for HIV-1 vaccines. Hum Vaccin Immunother 2020; 16:713-722. [PMID: 31584318 PMCID: PMC7227724 DOI: 10.1080/21645515.2019.1666957] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/19/2019] [Accepted: 09/05/2019] [Indexed: 12/13/2022] Open
Abstract
Despite 30 years of effort, we do not have an effective HIV-1 vaccine. Over the past decade, the HIV-1 vaccine field has shifted emphasis toward antibody-based vaccine strategies, following a lack of efficacy in CD8+ T-cell-based vaccine trials. Several lines of evidence, however, suggest that improved CD8+ T-cell-directed strategies could benefit an HIV-1 vaccine. First, T-cell responses often correlate with good outcomes in non-human primate (NHP) challenge models. Second, subgroup studies of two no-efficacy human clinical vaccine trials found associations between CD8+ T-cell responses and protective effects. Finally, improved strategies can increase the breadth and potency of CD8+ T-cell responses, direct them toward preferred epitopes (that are highly conserved and/or associated with viral control), or both. Optimized CD8+ T-cell vaccine strategies are promising in both prophylactic and therapeutic settings. This commentary briefly outlines some encouraging findings from T-cell vaccine studies, and then directly compares key features of some T-cell vaccine candidates currently in the clinical pipeline.
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Affiliation(s)
- Bette Korber
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Will Fischer
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
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Jones LD, Moody MA, Thompson AB. Innovations in HIV-1 Vaccine Design. Clin Ther 2020; 42:499-514. [PMID: 32035643 PMCID: PMC7102617 DOI: 10.1016/j.clinthera.2020.01.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/20/2019] [Accepted: 01/16/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE The field of HIV-1 vaccinology has evolved during the last 30 years from the first viral vector HIV gene insert constructs to vaccination regimens using a myriad of strategies. These strategies now include germline-targeting, lineage-based, and structure-guided immunogen design. This narrative review outlines the historical context of HIV vaccinology and subsequently highlights the scientific discoveries during the last 6 years that promise to propel the field forward. METHODS We conducted a search of 2 electronic databases, PubMed and EMBASE, for experimental studies that involved new HIV immunogen designs between 2013 and 2019. During the title and abstract reviews, publications were excluded if they were written in language other than English and/or were a letter to the editor, a commentary, or a conference-only presentation. We then used ClinicalTrials.gov to identify completed and ongoing clinical trials using these strategies. FINDINGS The HIV vaccinology field has undergone periods of significant growth during the last 3 decades. Findings elucidated in preclinical studies have revealed the importance of the interaction between the cellular and humoral immune system. As a result, several new rationally designed vaccine strategies have been developed and explored in the last 6 years, including native-like envelope trimers, nanoparticle, and mRNA vaccine design strategies among others. Several of these strategies have shown enough promise in animal models to progress toward first-in-human Phase I clinical trials. IMPLICATIONS Rapid developments in preclinical and early-phase clinical studies suggest that a tolerable and effective HIV vaccine may be on the horizon.
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Affiliation(s)
- Letitia D Jones
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
| | - M Anthony Moody
- Duke University School of Medicine and Duke Human Vaccine Institute, Durham, NC, USA
| | - Amelia B Thompson
- Duke University School of Medicine and Duke Human Vaccine Institute, Durham, NC, USA.
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Sui Y, Berzofsky JA. Myeloid Cell-Mediated Trained Innate Immunity in Mucosal AIDS Vaccine Development. Front Immunol 2020; 11:315. [PMID: 32184782 PMCID: PMC7058986 DOI: 10.3389/fimmu.2020.00315] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 02/07/2020] [Indexed: 12/12/2022] Open
Abstract
Trained innate immunity has recently emerged as a novel concept of innate immune cells, such as myeloid cells, exhibiting immune memory, and nonspecific heterologous immunity to protect against infections. The memory and specificity are mediated by epigenetic, metabolic, and functional reprogramming of the myeloid cells and myeloid progenitors (and/or NK cells) in the bone marrow and peripheral tissues such as gut and lung mucosa. A variety of agents, such as BCG, viruses, and their components, as well as TLR agonists, and cytokines have been shown to be involved in the induction of trained immunity. Since these agents have been widely used in AIDS vaccine development as antigen delivery vectors or adjuvants, myeloid cell mediated trained immunity might also play an important role in protecting against mucosal AIDS virus transmission or in control of virus replication in the major gut mucosal reservoir. Here we review the trained innate immunity induced by these vectors/adjuvants that have been used in AIDS vaccine studies and discuss their role in mucosal vaccine efficacy and possible utilization in AIDS vaccine development. Delineating the protective effect of the trained innate immunity mediated by myeloid cells will guide the design of novel AIDS vaccines.
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Affiliation(s)
- Yongjun Sui
- Vaccine Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Jay A Berzofsky
- Vaccine Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
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Yenkoidiok-Douti L, Jewell CM. Integrating Biomaterials and Immunology to Improve Vaccines Against Infectious Diseases. ACS Biomater Sci Eng 2020; 6:759-778. [PMID: 33313391 PMCID: PMC7725244 DOI: 10.1021/acsbiomaterials.9b01255] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite the success of vaccines in preventing many infectious diseases, effective vaccines against pathogens with ongoing challenges - such as HIV, malaria, and tuberculosis - remain unavailable. The emergence of new pathogen variants, the continued prevalence of existing pathogens, and the resurgence of yet other infectious agents motivate the need for new, interdisciplinary approaches to direct immune responses. Many current and candidate vaccines, for example, are poorly immunogenic, provide only transient protection, or create risks of regaining pathogenicity in certain immune-compromised conditions. Recent advances in biomaterials research are creating new potential to overcome these challenges through improved formulation, delivery, and control of immune signaling. At the same time, many of these materials systems - such as polymers, lipids, and self-assembly technologies - may achieve this goal while maintaining favorable safety profiles. This review highlights ways in which biomaterials can advance existing vaccines to safer, more efficacious technologies, and support new vaccines for pathogens that do not yet have vaccines. Biomaterials that have not yet been applied to vaccines for infectious disease are also discussed, and their potential in this area is highlighted.
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Affiliation(s)
- Lampouguin Yenkoidiok-Douti
- Fischell Department of Bioengineering, University of Maryland, College Park, 8278 Paint Branch Drive, College Park, MD, 20742, United States
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, Rockville, MD, 20852, United States
| | - Christopher M. Jewell
- Fischell Department of Bioengineering, University of Maryland, College Park, 8278 Paint Branch Drive, College Park, MD, 20742, United States
- Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, MD 21201, USA
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, MD 20742, United States
- Department of Microbiology and Immunology, University of Maryland Medical School, 685 West Baltimore Street, HSF-I Suite 380, Baltimore, MD, 21201, United States
- Marlene and Stewart Greenebaum Cancer Center, 22 S. Greene Street, Suite N9E17, Baltimore, MD 21201, United States
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Pantaleo G, Janes H, Karuna S, Grant S, Ouedraogo GL, Allen M, Tomaras GD, Frahm N, Montefiori DC, Ferrari G, Ding S, Lee C, Robb ML, Esteban M, Wagner R, Bart PA, Rettby N, McElrath MJ, Gilbert PB, Kublin JG, Corey L. Safety and immunogenicity of a multivalent HIV vaccine comprising envelope protein with either DNA or NYVAC vectors (HVTN 096): a phase 1b, double-blind, placebo-controlled trial. Lancet HIV 2019; 6:e737-e749. [PMID: 31601541 PMCID: PMC7156919 DOI: 10.1016/s2352-3018(19)30262-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 06/20/2019] [Accepted: 07/19/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND Up to now, immunisation regimens that have been assessed for development of HIV vaccines have included purified envelope (Env) protein among the boosting components of the regimen. We postulated that co-administration of Env protein with either a DNA or NYVAC vector during priming would result in early generation of antibody responses to the Env V1/V2 region, which are important markers for effective protection against infection. We aimed to assess the safety and immunogenicity of a multivalent HIV vaccine including either DNA or NYVAC vectors alone or in combination with Env glycoprotein (gp120) followed by a co-delivered NYVAC and Env protein boost. METHODS We did a single-centre, double-blind, placebo-controlled phase 1b trial at the Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland). We included healthy volunteers aged 18-50 years who were at low risk of HIV infection. We randomly allocated participants using computer-generated random numbers to one of four vaccination schedules or placebo (4:1), and within these schedules participants were allocated either active treatment (T1, T2, T3, and T4) or placebo (C1, C2, C3, and C4). T1 consisted of two doses of NYVAC vector followed by two doses of NYVAC vector and gp120 Env protein; T2 comprised four doses of NYVAC vector and gp120 Env protein; T3 was two doses of DNA vector followed by two doses of NYVAC vector and gp120 Env protein; and T4 was two doses of DNA vector and gp120 Env protein followed by two doses of NYVAC vector and gp120 Env protein. Placebo injections were matched to the corresponding active treatment group. Doses were administered by injection at months 0, 1, 3, and 6. Primary outcomes were safety and immunogenicity of the vaccine schedules. Immune response measures included cross-clade and epitope-specific binding antibodies, neutralising antibodies, and antibody-dependent cell-mediated cytotoxicity measured 2 weeks after the month 1, 3, and 6 vaccinations. This trial is registered with ClinicalTrials.gov, NCT01799954. FINDINGS Between Aug 23, 2012, and April 18, 2013, 148 healthy adult volunteers were screened for the trial, of whom 96 participants were enrolled. 20 individuals were allocated to each active treatment group (groups T1-4; n=80) and four were assigned to each placebo group (groups C1-4; n=16). Vaccines containing the NYVAC vector (groups T1 and T2) were associated with more frequent severe reactogenicity and more adverse events than were vaccines containing the DNA vector (groups T3 and T4). The most frequent adverse events judged related to study product were lymphadenopathy (n=9) and hypoaesthesia (n=2). Two participants, one in the placebo group and one in the DNA-primed T3 group, had serious adverse events that were judged unrelated to study product. One participant in the T3 group died from cranial trauma after a motor vehicle accident. Across the active treatment groups, IgG responses 2 weeks after the 6-month dose of vaccine were 74-95%. Early administration of gp120 Env protein (groups T2 and T4) was associated with a substantially earlier and higher area under the curve for gp120 Env binding, production of anti-V1/V2 and neutralising antibodies, and better antibody-response coverage over a period of 18 months, compared with vaccination regimens that delayed administration of gp120 Env protein until the 3-month vaccination (groups T1 and T3). INTERPRETATION Co-administration of gp120 Env protein components with DNA or NYVAC vectors during priming led to early and potent induction of Env V1/V2 IgG binding antibody responses. This immunisation approach should be considered for induction of preventive antibodies in future HIV vaccine efficacy trials. FUNDING National Institutes of Health, National Institute of Allergy and Infectious Diseases, and the Bill & Melinda Gates Foundation.
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Affiliation(s)
- Giuseppe Pantaleo
- Service of Immunology and Allergy, and Swiss Vaccine Research Institute, Lausanne University Hospital, Lausanne, Switzerland.
| | - Holly Janes
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shelly Karuna
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shannon Grant
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - G Laissa Ouedraogo
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; US Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mary Allen
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Georgia D Tomaras
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA
| | - Nicole Frahm
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Bill & Melinda Gates Medical Research Institute, Cambridge, MA, USA
| | - David C Montefiori
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA
| | - Guido Ferrari
- Department of Surgery, Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA
| | - Song Ding
- EuroVacc Foundation, Lausanne, Switzerland
| | - Carter Lee
- Global Solutions for Infectious Diseases, South San Francisco, CA, USA
| | - Merlin L Robb
- US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Mariano Esteban
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Ralf Wagner
- Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany; Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany
| | - Pierre-Alexandre Bart
- Service of Immunology and Allergy, and Swiss Vaccine Research Institute, Lausanne University Hospital, Lausanne, Switzerland
| | - Nils Rettby
- Service of Immunology and Allergy, and Swiss Vaccine Research Institute, Lausanne University Hospital, Lausanne, Switzerland
| | - M Juliana McElrath
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Peter B Gilbert
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - James G Kublin
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Lawrence Corey
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Safety and Immunogenicity of a Novel Recombinant Simian Adenovirus ChAdOx2 as a Vectored Vaccine. Vaccines (Basel) 2019; 7:vaccines7020040. [PMID: 31096710 PMCID: PMC6630572 DOI: 10.3390/vaccines7020040] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/30/2019] [Accepted: 05/08/2019] [Indexed: 12/16/2022] Open
Abstract
Adenovirus vectored vaccines are a highly effective strategy to induce cellular immune responses which are particularly effective against intracellular pathogens. Recombinant simian adenovirus vectors were developed to circumvent the limitations imposed by the use of human adenoviruses due to widespread seroprevalence of neutralising antibodies. We have constructed a replication deficient simian adenovirus-vectored vaccine (ChAdOx2) expressing 4 genes from the Mycobacterium avium subspecies paratuberculosis (AhpC, Gsd, p12 and mpa). Safety and T-cell immunogenicity results of the first clinical use of the ChAdOx2 vector are presented here. The trial was conducted using a ‘three-plus-three’ dose escalation study design. We demonstrate the vaccine is safe, well tolerated and immunogenic.
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Perciani CT, Farah B, Kaul R, Ostrowski MA, Mahmud SM, Anzala O, Jaoko W, MacDonald KS. Live attenuated varicella-zoster virus vaccine does not induce HIV target cell activation. J Clin Invest 2019; 129:875-886. [PMID: 30511963 DOI: 10.1172/jci124473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 11/27/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5-vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA. METHODS Healthy VZV-seropositive Kenyan women (n = 44) were immunized with high-dose live attenuated VZV vaccine, and we assessed the expression on CD4+ T cells isolated from blood, cervix, and rectum of IA markers including CD38 and HLA-DR and of markers of cell migration and tissue retention, as well as the concentration of genital and intestinal cytokines. A delayed-start group (n = 22) was used to control for natural variations in these parameters. RESULTS Although immunogenic, VZV vaccination did not result in significant difference in the frequency of cervical activated (HLA-DR+CD38+) CD4+ T cells (median 1.61%, IQR 0.93%-2.76%) at 12 weeks after vaccination when compared with baseline (median 1.58%, IQR 0.75%-3.04%), the primary outcome for this study. VZV vaccination also had no measurable effect on any of the IA parameters at 4, 8, and 12 weeks after vaccination. CONCLUSION This study provides the first evidence to our knowledge about the effects of VZV vaccination on human mucosal IA status and supports further evaluation of VZV as a potential vector for an HIV vaccine. TRIAL REGISTRATION ClinicalTrials.gov NCT02514018. FUNDING Primary support from the Canadian Institutes for Health Research (CIHR). For other sources, see Acknowledgments.
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Affiliation(s)
- Catia T Perciani
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Bashir Farah
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), University of Nairobi, Nairobi, Kenya
| | - Rupert Kaul
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,University Health Network, Toronto, Ontario, Canada
| | - Mario A Ostrowski
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Keenan Research Center, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Salaheddin M Mahmud
- Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Omu Anzala
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), University of Nairobi, Nairobi, Kenya.,Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | - Walter Jaoko
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), University of Nairobi, Nairobi, Kenya.,Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | | | - Kelly S MacDonald
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.,Section of Infectious Diseases, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.,Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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Veazey RS. Intestinal CD4 Depletion in HIV / SIV Infection. CURRENT IMMUNOLOGY REVIEWS 2019; 15:76-91. [PMID: 31431807 PMCID: PMC6701936 DOI: 10.2174/1573395514666180605083448] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 04/12/2018] [Accepted: 05/18/2018] [Indexed: 12/28/2022]
Abstract
Among the most significant findings in the pathogenesis of HIV infection was the discovery that almost total depletion of intestinal CD4+ T cells occurs rapidly after SIV or HIV infection, regardless of the route of exposure, and long before CD4+ T cell losses occur in blood or lymph nodes. Since these seminal discoveries, we have learned much about mucosal and systemic CD4+ T cells, and found several key differences between the circulating and intestinal CD4+ T cell subsets, both in phenotype, relative proportions, and functional capabilities. Further, specific subsets of CD4+ T cells are selectively targeted and eliminated first, especially cells critically important for initiating primary immune responses, and for maintenance of mucosal integrity (Th1, Th17, and Th22 cells). This simultaneously results in loss of innate immune responses, and loss of mucosal integrity, resulting in mucosal, and systemic immune activation that drives proliferation and activation of new target cells throughout the course of infection. The propensity for the SIV/HIV to infect and efficiently replicate in specific cells also permits viral persistence, as the mucosal and systemic activation that ensues continues to damage mucosal barriers, resulting in continued influx of target cells to maintain viral replication. Finally, infection and elimination of recently activated and proliferating CD4+ T cells, and infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that support active viral replication and evolution, and thus persistence in host tissue reservoirs, all of which continue to challenge our efforts to design effective vaccine or cure strategies.
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Affiliation(s)
- Ronald S. Veazey
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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Rahman MA, Robert-Guroff M. Accelerating HIV vaccine development using non-human primate models. Expert Rev Vaccines 2018; 18:61-73. [PMID: 30526159 DOI: 10.1080/14760584.2019.1557521] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION The search for a preventative HIV vaccine is ongoing after three decades of research. Contributions of non-human primate (NHP) models to this research are irrefutable, however interpreting data obtained for translation to humans has been problematic. As knowledge concerning NHP models has accumulated, their utility and value in assessing immunogenicity and efficacy of novel vaccines have become apparent. NHP models have become a critical component of vaccine design. AREAS COVERED Beginning with early vaccine studies, we trace the development and evolution of NHP models concurrent with changes in HIV vaccine concepts and in response to their ability to predict clinical trial efficacy. The value of NHP studies in guiding vaccine design is highlighted along with their importance in opening new areas of investigation and facilitating movement of promising approaches into the clinic. EXPERT COMMENTARY Due to their close relatedness to humans, NHPs are an excellent choice for immunogenicity studies. The ability of NHP models to predict clinical efficacy has improved with the introduction of low-dose challenge viruses and recognition of confounding variables in study outcomes. Use of NHP models has opened new research areas with outstanding potential for generating vaccine efficacy against HIV and other infectious agents.
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Affiliation(s)
- Mohammad Arif Rahman
- a Vaccine Branch, Center for Cancer Research , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Marjorie Robert-Guroff
- a Vaccine Branch, Center for Cancer Research , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
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Wu T, Ma F, Ma X, Jia W, Pan E, Cheng G, Chen L, Sun C. Regulating Innate and Adaptive Immunity for Controlling SIV Infection by 25-Hydroxycholesterol. Front Immunol 2018; 9:2686. [PMID: 30524435 PMCID: PMC6262225 DOI: 10.3389/fimmu.2018.02686] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/31/2018] [Indexed: 11/13/2022] Open
Abstract
Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection. CH25H expression was interferon-dependent and induced by SIV infection in monkey-derived macrophages and PBMC cells, and 25-HC inhibited SIV infection both in permissive cell lines and primary monkey lymphocytes. 25-HC also strongly inhibited bacterial lipopolysaccharide (LPS)-stimulated inflammation and restricted mitogen-stimulated proliferation in primary monkey lymphocytes. Strikingly, 25-HC promoted SIV-specific IFN-γ-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-α cytokines in vaccinated mice. In addition, 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. Collectively, 25-HC modulated both innate and adaptive immune responses toward inhibiting HIV/SIV infection. This study provides insights into improving vaccination and immunotherapy regimes against HIV-1 infection.
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Affiliation(s)
- Tongjin Wu
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangdong, China.,State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,School of Life Sciences, Anhui University, Hefei, China
| | - Feng Ma
- Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Xiuchang Ma
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Weizhe Jia
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangdong, China.,College of Bioscience and Bioengineering, Hebei University of Science and Technology, Shijiazhuang, China
| | - Enxiang Pan
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Genhong Cheng
- Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China.,Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Ling Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangdong, China.,State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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Progress in Adenoviral Capsid-Display Vaccines. Biomedicines 2018; 6:biomedicines6030081. [PMID: 30049954 PMCID: PMC6165093 DOI: 10.3390/biomedicines6030081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/20/2018] [Accepted: 07/23/2018] [Indexed: 12/31/2022] Open
Abstract
Adenoviral vectored vaccines against infectious diseases are currently in clinical trials due to their capacity to induce potent antigen-specific B- and T-cell immune responses. Heterologous prime-boost vaccination with adenoviral vector and, for example, adjuvanted protein-based vaccines can further enhance antigen-specific immune responses. Although leading to potent immune responses, these heterologous prime-boost regimens may be complex and impact manufacturing costs limiting efficient implementation. Typically, adenoviral vectors are engineered to genetically encode a transgene in the E1 region and utilize the host cell machinery to express the encoded antigen and thereby induce immune responses. Similarly, adenoviral vectors can be engineered to display foreign immunogenic peptides on the capsid-surface by insertion of antigens in capsid proteins hexon, fiber and protein IX. The ability to use adenoviral vectors as antigen-display particles, with or without using the genetic vaccine function, greatly increases the versatility of the adenoviral vector for vaccine development. This review describes the application of adenoviral capsid antigen-display vaccine vectors by focusing on their distinct advantages and possible limitations in vaccine development.
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Dietrich JJ, Lazarus E, Andrasik M, Hornschuh S, Otwombe K, Morgan C, Isaacs AJ, Huang Y, Laher F, Kublin JG, Gray GE. Mobile Phone Questionnaires for Sexual Risk Data Collection Among Young Women in Soweto, South Africa. AIDS Behav 2018; 22:2312-2321. [PMID: 29594618 DOI: 10.1007/s10461-018-2080-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Recall and social desirability bias undermine self-report of paper-and-pencil questionnaires. Mobile phone questionnaires may overcome these challenges. We assessed and compared sexual risk behavior reporting via in-clinic paper-and-pencil and mobile phone questionnaires. HVTN 915 was a prospective cohort study of 50 adult women in Soweto, who completed daily mobile phone, and eight interviewer-administered in-clinic questionnaires over 12 weeks to assess sexual risk. Daily mobile phone response rates were 82% (n = 3486/4500); 45% (n = 1565/3486) reported vaginal sex (median sex acts 2 (IQR: 1-3)) within 24 h and 40% (n = 618/1565) consistent condom. Vaginal sex reporting was significantly higher via mobile phone across all visits (p < 0.0001). There was no significant difference in condom use reporting by mobile phone and in-clinic paper-based questionnaires across all visits (p = 0.5134). The results show high adherence and reporting of sex on the mobile phone questionnaire. We demonstrate feasibility in collecting mobile phone sexual risk data.
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Affiliation(s)
- Janan J Dietrich
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, PO BOX 114, Diepkloof, Soweto, Johannesburg, 1864, South Africa.
| | - Erica Lazarus
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, PO BOX 114, Diepkloof, Soweto, Johannesburg, 1864, South Africa
| | - Michele Andrasik
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stefanie Hornschuh
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, PO BOX 114, Diepkloof, Soweto, Johannesburg, 1864, South Africa
| | - Kennedy Otwombe
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, PO BOX 114, Diepkloof, Soweto, Johannesburg, 1864, South Africa
| | - Cecilia Morgan
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Abby J Isaacs
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Yunda Huang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Fatima Laher
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, PO BOX 114, Diepkloof, Soweto, Johannesburg, 1864, South Africa
| | - James G Kublin
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Global Health, University of Washington, Seattle, WA, USA
| | - Glenda E Gray
- Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, PO BOX 114, Diepkloof, Soweto, Johannesburg, 1864, South Africa
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- South African Medical Research Council, Cape Town, South Africa
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Lambe T, Bowyer G, Ewer KJ. A review of Phase I trials of Ebola virus vaccines: what can we learn from the race to develop novel vaccines? Philos Trans R Soc Lond B Biol Sci 2017; 372:rstb.2016.0295. [PMID: 28396468 PMCID: PMC5394635 DOI: 10.1098/rstb.2016.0295] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2016] [Indexed: 11/23/2022] Open
Abstract
Sporadic outbreaks of Ebola virus infection have been documented since the mid-Seventies and viral exposure can lead to lethal haemorrhagic fever with case fatalities as high as 90%. There is now a comprehensive body of data from both ongoing and completed clinical trials assessing various vaccine strategies, which were rapidly advanced through clinical trials in response to the 2013–2016 Ebola virus disease (EVD) public health emergency. Careful consideration of immunogenicity post vaccination is essential but has been somewhat stifled because of the wide array of immunological assays and outputs that have been used in the numerous clinical trials. We discuss here the different aspects of the immune assays currently used in the Phase I clinical trials for Ebola virus vaccines, and draw comparisons across the immune outputs where possible; various trials have examined both cellular and humoral immunity in European and African cohorts. Assessment of the safety data, the immunological outputs and the ease of field deployment for the various vaccine modalities will help both the scientific community and policy-makers prioritize and potentially license vaccine candidates. If this can be achieved, the next outbreak of Ebola virus, or other emerging pathogen, can be more readily contained and will not have such widespread and devastating consequences. This article is part of the themed issue ‘The 2013–2016 West African Ebola epidemic: data, decision-making and disease control’.
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Affiliation(s)
- Teresa Lambe
- The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK
| | - Georgina Bowyer
- The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK
| | - Katie J Ewer
- The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK
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Huang YM, Hong XZ, Xu JH, Luo JX, Mo HY, Zhao HL. Autoimmunity and dysmetabolism of human acquired immunodeficiency syndrome. Immunol Res 2017; 64:641-52. [PMID: 26676359 DOI: 10.1007/s12026-015-8767-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Acquired immunodeficiency syndrome (AIDS) remains ill-defined by lists of symptoms, infections, tumors, and disorders in metabolism and immunity. Low CD4 cell count, severe loss of body weight, pneumocystis pneumonia, and Kaposi's sarcoma are the major disease indicators. Lines of evidence indicate that patients living with AIDS have both immunodeficiency and autoimmunity. Immunodeficiency is attributed to deficits in the skin- and mucosa-defined innate immunity, CD4 T cells and regulatory T cells, presumably relating human immunodeficiency virus (HIV) infection. The autoimmunity in AIDS is evident by: (1) overproduction of autoantibodies, (2) impaired response of CD4 cells and CD8 cells, (3) failure of clinical trials of HIV vaccines, and (4) therapeutic benefits of immunosuppression following solid organ transplantation and bone marrow transplantation in patients at risk of AIDS. Autoantibodies are generated in response to antigens such as debris and molecules de novo released from dead cells, infectious agents, and catabolic events. Disturbances in metabolic homeostasis occur at the interface of immunodeficiency and autoimmunity in the development of AIDS. Optimal treatments favor therapeutics targeting on the regulation of metabolism to restore immune homeostasis.
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Affiliation(s)
- Yan-Mei Huang
- Department of Immunology, Center for Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin, 541004, China
| | - Xue-Zhi Hong
- Department of Immunology, Center for Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin, 541004, China. .,Department of Rheumatology and Immunology, The Affiliated Hospital of the Guilin Medical University, Guilin, 541004, China.
| | - Jia-Hua Xu
- Fangchenggang Hospital of Traditional Chinese Medicine, Fangchenggang, 538021, Guangxi, China
| | - Jiang-Xi Luo
- Department of Immunology, Center for Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin, 541004, China
| | - Han-You Mo
- Department of Rheumatology and Immunology, The Affiliated Hospital of the Guilin Medical University, Guilin, 541004, China
| | - Hai-Lu Zhao
- Department of Immunology, Center for Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin, 541004, China.,Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin, 541004, China
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Veazey RS, Lackner AA. Nonhuman Primate Models and Understanding the Pathogenesis of HIV Infection and AIDS. ILAR J 2017; 58:160-171. [PMID: 29228218 PMCID: PMC5886333 DOI: 10.1093/ilar/ilx032] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/01/2017] [Accepted: 11/04/2017] [Indexed: 12/16/2022] Open
Abstract
Research using nonhuman primates (NHPs) as models for human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) has resulted in tremendous achievements not only in the prevention and treatment of HIV, but also in biomedical research more broadly. Once considered a death sentence, HIV infection is now fairly well controlled with combination antiretroviral treatments, almost all of which were first tested for efficacy and safety in nonhuman primates or other laboratory animals. Research in NHP has led to "dogma changing" discoveries in immunology, infectious disease, and even our own genetics. We now know that many of our genes are retroviral remnants, or developed in response to archaic HIV-like retroviral infections. Early studies involving blood from HIV patients and in experiments in cultured tissues contributed to confusion regarding the cause of AIDS and impeded progress in the development of effective interventions. Research on the many retroviruses of different NHP species have broadened our understanding of human immunology and perhaps even our origins and evolution as a species. In combination with recent advances in molecular biology and computational analytics, research in NHPs has unique potential for discoveries that will directly lead to new cures for old human and animal diseases, including HIV/AIDS.
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Affiliation(s)
- Ronald S Veazey
- Ronald S. Veazey, DVM, PhD, is chair of the Division of Comparative Pathology at the Tulane National Primate Research Center and professor in the Department of Pathology and Laboratory Medicine at the Tulane University School of Medicine. Dr. Andrew Lackner, DVM, PhD is director of the Tulane National Primate Research Center and professor of the Department of Microbiology and Pathology and Laboratory Medicine at the Tulane University School of Medicine
| | - Andrew A Lackner
- Ronald S. Veazey, DVM, PhD, is chair of the Division of Comparative Pathology at the Tulane National Primate Research Center and professor in the Department of Pathology and Laboratory Medicine at the Tulane University School of Medicine. Dr. Andrew Lackner, DVM, PhD is director of the Tulane National Primate Research Center and professor of the Department of Microbiology and Pathology and Laboratory Medicine at the Tulane University School of Medicine
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Mennechet FJD, Eichholz K, Tran TTP, Kremer EJ. [Anti-adenovirus humoral immunity: impact on dendritic cell activation]. Med Sci (Paris) 2017; 33:582-585. [PMID: 28990553 DOI: 10.1051/medsci/20173306008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Franck J D Mennechet
- Institut de génétique moléculaire de Montpellier (IGMM), CNRS, université de Montpellier, Montpellier, France
| | - Karsten Eichholz
- Institut de génétique moléculaire de Montpellier (IGMM), CNRS, université de Montpellier, Montpellier, France
| | - Thi Thu Phuong Tran
- Institut de génétique moléculaire de Montpellier (IGMM), CNRS, université de Montpellier, Montpellier, France
| | - Eric J Kremer
- Institut de génétique moléculaire de Montpellier (IGMM), CNRS, université de Montpellier, Montpellier, France
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Abstract
Despite major advances in antiretroviral therapy against HIV-1, an effective HIV vaccine is urgently required to reduce the number of new cases of HIV infections in the world. Vaccines are the ultimate tool in the medical arsenal to control and prevent the spread of infectious diseases such as HIV/AIDS. Several failed phase-IIb to –III clinical vaccine trials against HIV-1 in the past generated a plethora of information that could be used for better designing of an effective HIV vaccine in the future. Most of the tested vaccine candidates produced strong humoral responses against the HIV proteins; however, failed to protect due to: 1) the low levels and the narrow breadth of the HIV-1 neutralizing antibodies and the HIV-specific antibody-dependent Fc-mediated effector activities, 2) the low levels and the poor quality of the anti-HIV T-cell responses, and 3) the excessive responses to immunodominant non-protective HIV epitopes, which in some cases blocked the protective immunity and/or enhanced HIV infection. The B-cell epitopes on HIV for producing broadly neutralizing antibodies (bNAbs) against HIV have been extensively characterized, and the next step is to develop bNAb epitope immunogen for HIV vaccine. The bNAb epitopes are often conformational epitopes and therefore more difficult to construct as vaccine immunogen and likely to include immunodominant non-protective HIV epitopes. In comparison, T-cell epitopes are short linear peptides which are easier to construct into vaccine immunogen free of immunodominant non-protective epitopes. However, its difficulty lies in identifying the T-cell epitopes conserved among HIV subtypes and induce long-lasting, potent polyfunctional T-cell and cytotoxic T lymphocyte (CTL) activities against HIV. In addition, these protective T-cell epitopes must be recognized by the HLA prevalent in the country(s) targeted for the vaccine trial. In conclusion, extending from the findings from previous vaccine trials, future vaccines should combine both T- and B-cell epitopes as vaccine immunogen to induce multitude of broad and potent immune effector activities required for sterilizing protection against global HIV subtypes.
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Affiliation(s)
- Bikash Sahay
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, P.O. Box 110880, Gainesville, FL 32611-0880, USA
| | - Cuong Q Nguyen
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, P.O. Box 110880, Gainesville, FL 32611-0880, USA
| | - Janet K Yamamoto
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, P.O. Box 110880, Gainesville, FL 32611-0880, USA
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Abstract
PURPOSE OF REVIEW Only four HIV-1 vaccine concepts have been tested in six efficacy trials with no product licensed to date. Several scientific and programmatic lessons can be learned from these studies generating new hypotheses and guiding future steps. RECENT FINDINGS RV144 [ALVAC-HIV (canarypox vector) and AIDSVAX B/E (bivalent gp120 HIV-1 subtype B and CRF01_AE)] remains the only efficacy trial that demonstrated a modest vaccine efficacy, which led to the identification of immune correlates of risk. Progress on subtype-specific, ALVAC (canarypox vector) and gp120 vaccine prime-boost approaches has been slow, but we are finally close to the launch of an efficacy study in Africa in 2016. The quest of a globally effective HIV-1 vaccine has led to the development of new approaches. Efficacy studies of combinations of Adenovirus type 26 (Ad26)/Modified Vaccinia Ankara (MVA)/gp140 vaccines with mosaic designs will enter efficacy studies mid-2017 and cytomegalovirus (CMV)-vectored vaccines begin Phase I studies at the same time. Future HIV-1 vaccine efficacy trials face practical challenges as effective nonvaccine prevention programs are projected to decrease HIV-1 incidence. SUMMARY An HIV-1 vaccine is urgently needed. Increased industry involvement, mobilization of resources, expansion of a robust pipeline of new concepts, and robust preclinical challenge studies will be essential to accelerate efficacy testing of next generation HIV-1 vaccine candidates.
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Abstract
A key unresolved challenge for developing an effective HIV‐1 vaccine is the discovery of strategies to elicit immune responses that are able to cross‐protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV‐1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine‐elicited T‐cell responses, which contribute to the control of HIV‐1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross‐reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV‐1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage‐based design strategies to illustrate how such in‐depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.
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Affiliation(s)
- Bette Korber
- Theoretical Biology and Biophysics, T6, Los Alamos National Laboratory, Los Alamos, NM, USA.,New Mexico Consortium, Los Alamos, NM, USA
| | - Peter Hraber
- Theoretical Biology and Biophysics, T6, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Kshitij Wagh
- Theoretical Biology and Biophysics, T6, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Beatrice H Hahn
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
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Tomaras GD, Plotkin SA. Complex immune correlates of protection in HIV-1 vaccine efficacy trials. Immunol Rev 2017; 275:245-261. [PMID: 28133811 DOI: 10.1111/imr.12514] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine-mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate-thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine.
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Affiliation(s)
- Georgia D Tomaras
- Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Duke Human Vaccine Institute, Durham, NC, USA
| | - Stanley A Plotkin
- Vaxconsult, Doylestown, PA, USA.,University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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Hinkula J, Petkov S, Ljungberg K, Hallengärd D, Bråve A, Isaguliants M, Falkeborn T, Sharma S, Liakina V, Robb M, Eller M, Moss B, Biberfeld G, Sandström E, Nilsson C, Markland K, Blomberg P, Wahren B. HIVIS-DNA or HIVISopt-DNA priming followed by CMDR vaccinia-based boosts induce both humoral and cellular murine immune responses to HIV. Heliyon 2017; 3:e00339. [PMID: 28721397 PMCID: PMC5496381 DOI: 10.1016/j.heliyon.2017.e00339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 06/19/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In order to develop a more effective prophylactic HIV-1 vaccine it is important optimize the components, improve Envelope glycoprotein immunogenicity as well as to explore prime-boost immunization schedules. It is also valuable to include several HIV-1 subtype antigens representing the world-wide epidemic. METHODS HIVIS-DNA plasmids which include Env genes of subtypes A, B and C together with Gag subtypes A and B and RTmut/Rev of subtype B were modified as follows: the Envelope sequences were shortened, codon optimized, provided with an FT4 sequence and an immunodominant region mutated. The reverse transcriptase (RT) gene was shortened to contain the most immunogenic N-terminal fragment and fused with an inactivated viral protease vPR gene. HIVISopt-DNA thus contains fewer plasmids but additional PR epitopes compared to the native HIVIS-DNA. DNA components were delivered intradermally to young Balb/c mice once, using a needle-free Biojector® immediately followed by dermal electroporation. Vaccinia-based MVA-CMDR boosts including Env gene E and Gag-RT genes A were delivered intramuscularly by needle, once or twice. RESULTS Both HIVIS-DNA and HIVISopt-DNA primed humoral and cell mediated responses well. When boosted with heterologous MVA-CMDR (subtypes A and E) virus inhibitory neutralizing antibodies were obtained to HIV-1 subtypes A, B, C and AE. Both plasmid compositions boosted with MVA-CMDR generated HIV-1 specific cellular responses directed against HIV-1 Env, Gag and Pol, as measured by IFNγ ELISpot. It was shown that DNA priming augmented the vector MVA immunological boosting effects, the HIVISopt-DNA with a trend to improved (Env) neutralization, the HIVIS-DNA with a trend to better (Gag) cell mediated immune reponses. CONCLUSIONS HIVIS-DNA was modified to obtain HIVISopt-DNA that had fewer plasmids, and additional epitopes. Even with one DNA prime followed by two MVA-CMDR boosts, humoral and cell-mediated immune responses were readily induced by priming with either DNA construct composition. Priming by HIV-DNA augmented neutralizing antibody responses revealed by boosting with the vaccinia-based heterologous sequences. Cellular and antibody responses covered selected strains representing HIV-1 subtypes A, B, C and CRF01_AE. We assume this is related to the inclusion of heterologous full genes in the vaccine schedule.
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Affiliation(s)
- J Hinkula
- Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - S Petkov
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - K Ljungberg
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - D Hallengärd
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - A Bråve
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - M Isaguliants
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - T Falkeborn
- Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
| | - S Sharma
- Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden
| | - V Liakina
- Faculty of Medicine, Vilnius University 2, 08661 Vilnius, Lithuania
| | - M Robb
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, 20892 MD, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, 20892 MD, USA
| | - M Eller
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, 20892 MD, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, 20892 MD, USA
| | - B Moss
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892 MD, USA
| | - G Biberfeld
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - E Sandström
- Department of South Hospital, Karolinska Institutet, 11883 Stockholm, Sweden
| | - C Nilsson
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - K Markland
- Clinical Research Center and Vecura, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - P Blomberg
- Clinical Research Center and Vecura, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - B Wahren
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
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